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Massachusetts Institute of TechnologMassachusetts Institute of Technology

Brigham and Women’s HospitalBrigham and Women’s HospitalVA Boston Healthcare SystemVA Boston Healthcare System

2.79J/3.96J/20.441/HST522J2.79J/3.96J/20.441/HST522J

BIOMATERIALSBIOMATERIALS--TISSUE INTERATISSUE INTERA

oo s or n erstan ng t e o ecu aoo s or n erstan ng t e o ecu aand Physiological Bases of the Tissue Reand Physiological Bases of the Tissue Re

ImplantsImplants

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Tissue* + Biomaterial**

Cell + Matrix**

BIOMATERIALS-TISSUE

INTERACTIONS

* Structure comprising cells of the same type

** Solid surface

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Cell + Extracellular MatrCell + Extracellular Matr

In Tissue Engineering ScaffoIn Tissue Engineering Scaffo

Cell + Biomaterial ScaffolCell + Biomaterial Scaffol

CELL-MATRIX INTERACTIO

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•• Control VolumeControl Volume

•• Unit Cell ProcessesUnit Cell Processes

••

•• Tissue Formation and RemodelinTissue Formation and Remodelin

•• oun ea ngoun ea ng n von vo

CONCEPTS FOR UNDERSTAND

BIOMATERIALS-TISSUE INTERA

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Articular Cartilage

Matrix

Extracellular

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40minChondrocytes (P2 Canine) in

Type I Collagen-GAG Scaffol

2 1

3

Courtesy Elsevier, Inc., http://www.sciencedirect.com. Used with permission.

“Co

http://www.sciencedirect.com./

http://www.sciencedirect.com./

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SolubleSoluble

AA

+ So+ SoCell + MatrixCell +

Product

Matrix

Product(Regulator)(Regulator)

UNIT CELL PROCESSES

Concept of a “Control Volume” aroun

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SolubleSoluble

+ So+ SoCell + Matrix

Product

Cell + Matrix


UNIT CELL PROCESSES


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SolubleSolubleMechanicalMechanical

AALoading (Strain); Subject 2.785Loading (Strain); Subject 2.785

+ So+ SoCell + Matrix

Product

Cell + Matrix


UNIT CELL PROCESSES


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••





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•• MitosisMitosis

•• MigrationMigration

•• SynthesisSynthesis•• ontract onontract on

•• EndocytosisEndocytosis

UNIT CELL PROCESSES

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UNIT CELL PROCESSES

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UNIT CELL PROCESSES

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COLLAGEN-GAG MATRICES: MODEL BIOM

(ANALOGS OF EXTRACELLULAR MA

Investigation of cell interactions (UCPs)

• Type I (bovi

• ype por

• Chondroitin

1mm

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••

Can provide insights into interrelatioCan provide insights into interrelatioamong cell processes.among cell processes.

–– How do mitosis and synthesis interrelateHow do mitosis and synthesis interrelate

––How do mitosis and synthesis relate toHow do mitosis and synthesis relate to

–– How does migration relate to contractionHow does migration relate to contraction

••

CELL – MATRIX INTERACTIONS

COLLAGEN-GAG MATRICES IN V

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Chondrocytes (Passage 2 Canine)

T I ll n- A M rix

Live cell imaging

for a period of 5

hours.

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••

••

MigrationMigration •• yn es syn es s

•• ContractionContraction

CELL – MATRIX INTERACTI

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Chondrocyte (P2 Canine) in a Type I Collagen-G

Mitosis

Photo removed due to

copyright restrictions.

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60 Mean SEM

40 )

30 A

( u

20 D

Effects of Cross-Linking on Chondrocyte P

in Collagen-GAG Matrices

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CELL ± MATRIX INTERACTIONS

Mitosis

Migration

Synthesis

Contraction

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Fibroblasts Migrate Away from Soft SubNIH 3T3 cells are plated on polyacrylamide substrates with a transi

soft side is marked with fluorescent beads (to the left). Cells tur

substrate as they approach the boundary from the stiff side, by re

lamellipodium that crossed the boundary.

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Fibroblasts Migrate Toward Stiff SubstrNIH 3T3 cells are plated on polyacrylamide substrates with a transit

soft side is marked with fluorescent beads (to the left). Cells turn to

stiff side as they approach the boundary from the soft side, by exp

toward the boundary into a leading lamellipodium

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Fibroblasts Migrate Toward Stretching FNIH 3T3 cells are plated on polyacrylamide substrates. Pulling fo

inserting a blunted needle in the substrate near the trailing end of t

the needle away from the cell. Cells switch the direction of migra

secondary protrusions toward the needle into a leading lam

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Fibroblasts Migrate Away from CompressinNIH 3T3 cells are plated on polyacrylamide substrates. Pushing fo

inserting a blunted needle in the substrate near the leading edge of

and moving the needle toward the cell. Cells switch the direction

retracting the leading lamellipodium.

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Migration of Epithelial Cells In Vitro in a Wound H

100 m

© 2001 L. C. Santy and J. E. Casanova. License CC BY-NC-SA..

http://dx.doi.org/10.1083/jcb.200104019



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40min

2 1

3

Chondrocytes (P2 Canine) in a

GAG Matrix: Migration and

J. Zaleskas, et al .,Biomat. 25:1299 (2004)

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Diagram removed due to copyright restrictionsg. n a r , ney nt. : .

Schematic of the modulation of microvascularendothelial cell phenotype during angiogenesis

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••


CELL –

MATRIX INTERACT

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Protein Synthesis;Protein Synthesis;Proline Incor orationProline Incor oration

ProteoglyProteogly

.15.15

D N

A

D N

A

0.030.03

DHTDHT

UVUV

0.10.1

o u r /

o u r /

0.020.02EDCEDC

0.050.05

n m o l /

n m o l / 0.010.01

00

Effects of Cross-Linking on Chondrocyte in Collagen-GAG Matrices

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CELLCELL – –MATRIX INTERACTMATRIX INTERACT



••


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-smooth muscle actin-fusion peptide (SMA-FP) inhibits the tensio

fibroblasts on silicone substrates. After washing our of the FP, cells

See video at

http://jcb.rupress.org/content/suppl/2002/05/03/jcb.20020

http://jcb.rupress.org/content/suppl/2002/05/03/jcb.200201049.DC1/1.html

http://jcb.rupress.org/content/suppl/2002/05/03/jcb.200201049.DC1/1.html

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Chondrocytes (P2 Canine) in a Typ

Colla en-GAG Matrix: Contracti

J. Zaleskas, et al .,

Biomat. 25:1299 (2004)

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40 min

300 minCourtesy Elsevier, Inc., http://www.sciencedirect.com. Used with permission.

40 min

http://www.sciencedirect.com/

http://www.sciencedirect.com/

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Non-Seeded: 8 days Cell-Seeded: 8 d

mm

Non-Seeded: 8 days- Cell-Seeded: 8 da- -

10mm

Non-Seeded and Cell-Seeded

Collagen-GAG Scaffolds

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Adult canine articular chondrocytes (passage 3) c

colla en-GAG matrix, reflected in the decrease

100 Mean SE

80 90

e t

e r

70

l D i a

50 r i g i n

40

Adult canine articular chondrocytes (passage 3) con

collagen-GAG matrix, reflected in the decrease in

H

h

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Human Articular Chondrocytes in MonolIH - Green: -smooth muscle actin; Orange: ty

Chondrocytes

express the gene

Smooth Muscle Actin Immunohistoch

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-Smooth Muscle Actin Immunohistoch

of Human Articular Cartilage

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••Articular chondrocyteArticular chondrocyte

•• OsteoblastOsteoblastOsteoblastOsteoblast

•• Meniscus fibroblast and fibrochoMeniscus fibroblast and fibrocho

•• Intervertebral disc fibroblast andIntervertebral disc fibroblast andfibrochondrocytefibrochondrocyte

•• Ligament fibroblastLigament fibroblast

•• Tendon fibroblastTendon fibroblast

MUSCULOSKELETAL CELLS THAT CA

a-SMOOTH MUSCLE ACTIN AND CAN C

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Musculoskeletal Connective Tissue Musculoskeletal Connective Tissue

•• HealingHealing Closure of woundsClosure of woundsskin wounds and bonskin wounds and bon

•• Disease processesDisease processes Contracture (DupuytrContracture (Dupuytr

••

Tissue formationTissue formation Modeling of ECM arcModeling of ECM arcand remodelingand remodeling ((e.g.,e.g., crimp in ligamencrimp in ligamen

POSSIBLE ROLES FOR -SMOOTH

ACTIN-ENABLED CONTRACTION

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••



CONCEPTS FOR UNDERSTANDIN


TYPES OF TISSUES

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YesYes

Connective TissuesConnective Tissues

•• BoneBone √√

•• Articular Cartilage,Articular Cartilage,Ligament, IntervertebralLigament, Intervertebral

Epithelia (e.g., epidermis)Epithelia (e.g., epidermis) √√

MuscleMuscle

TYPES OF TISSUESWhich Tissues Can Regenerate Spon

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ee a r xa r x

ConnectiveConnectiveTissueTissue

EpitheliaEpithelia

usc eusc e

BIOMATERIALS-TISSUE

INTERACTIONS

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SolubleSolubleMechanicalMechanical

AALoading (Strain)Loading (Strain)

Cell + Matrix Product + So

(Regulator)

UNIT CELL PROCESSES

Concept of a “Control Volume” arou

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ConnectiveConnective AdhesionAdhesion

EpitheliaEpithelia

MuscleMuscle

ProteinProtein

CollagenCollagen

erveerve

BIOMATERIALS-TISSUE

INTERACTIONS

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ConnectiveConnective

TissueTissue AdhesionAdhesion

EpitheliaEpithelia

MuscleMuscleCollagenCollagen

BiomaterialBiomaterial

erveerveI t iI t i

BIOMATERIALS-TISSUE

INTERACTIONS

Chinese hamster ovary cell migration in a wound

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Chinese hamster ovary cell migration in a wound

C. W

2:21K.A

Cell

CHO cellsexpress the

α5 β 1 but not

α4 β 1 integrin

Photos removed due to copyright restrictions.

Figure 3 in Watters, C. Cell Biol. Ed . 2:210 (2003

Image and links to associated videos athttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC256980/f

Migration of fibroblast-like fibrosarcoma c

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC256980/figure/F3/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC256980/figure/F3/

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Migration of fibroblast like fibrosarcoma c

3-D collagen lattice

K.Bi

Reduction of migration speed and

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UCPUCP

MitosisMitosisConnectiveConnectiveyn es syn es s

MigrationMigration

ContractionContraction

TissueTissue

EpitheliaEpithelia

MuscleMuscle EndocytosisEndocytosisNerveNerve

“UNIT CELL PROCESSE

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UCPUCP

MitosisMitosis Cell pCell p

S nthesisS nthesis MatriMatriConnectiveConnective

enzymenzym

MigrationMigration TransTransEpitheliaEpithelia

MuscleMuscle

erveerve

“UNIT CELL PROCESSES

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RegulatorRegulator

Cell + Matrix Product +Cell + Matrix Product + RR

UCPUCP

MitosisMitosis

SynthesisSynthesisConnectiveConnective

TissueTissue

CC

(G(G

C iC iEpitheliaEpithelia

“UNIT CELL PROCESSE

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•• Cytokines/Growth FactorsCytokines/Growth Factors

––http://themedicalbiochemistrypage.ohttp://themedicalbiochemistrypage.o

factors.htmlfactors.html–– (previously:(previously:

http://web.indstate.edu/thcme/mwkihttp://web.indstate.edu/thcme/mwki

REGULATORS

http://themedicalbiochemistrypage.org/growth-factors.html




http://web.indstate.edu/thcme/mwking/growth-factors.html




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RegulatorRegulator Mechanical Force (Strain)Mechanical Force (Strain)

Cell + Matrix Product + RCell + Matrix Product + R

UCPUCP

MitosisMitosis


TissueTissue

AdhesionAdhesionCC

(G(G

MigrationMigrationEpitheliaEpithelia C llC ll


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RegulatorRegulator Mechanical Force (Strain)Mechanical Force (Strain)

Cell + Matrix Product + RCell + Matrix Product + R

UCPUCP

MitosisMitosis


TissueTissue

AdhesionAdhesion

MigrationMigrationEpitheliaEpithelia C llC ll


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RegulatorRegulator (TGF(TGF-- 1)1)

Cell + Matrix Product + Cell + Matrix Product + MitosisMitosis


TissueTissue

AdhesionAdhesion

ProteinProtein

CC

((

Matrix strainMatrix strain

(contracture/(contracture/

shrinka eshrinka ep e ap e a CollagenCollagen


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TGFTGF-- 11

ContractionContractionFibroblast + Collagen ContractFibroblast + Collagen Contract


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••




BIOMATERIALS TISSUE INTERA-

+FGF 2

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TISSUE FO

IN V

Canine chondrocytes grown in

a type II collagen-GAG

scaffold for 2 weeks.

(Safranin O stain for GAGs)

+FGF-2

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••





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InjuryInjury4 T4 T

CC

(Vascularized tissue)(Vascularized tissue)

eparat veeparat veProcessProcess

Regeneration*Regeneration* Repair (SRepair (S

WOUND HEALING

Roots of Tissue Engineering

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Surgical ImplantationSurgical Implantation

Vascular ResponseVascular ResponseClottingClotting

PhagocytosisPhagocytosis

NeovascularizationNeovascularization

AcuteAcute

InflammationInflammation GranGran

TT

Tissue of Labile and Stable CellsTissue of Labile and Stable Cells Tissue of PermaTissue of PermaImplant MovementImplant Movement

rameworramewor rameworramewor carr ncarr n

RESPONSE TO IMPLANTS

WOUND HEALING

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MIT OpenCourseWarehttp://ocw.mit.edu

20.441J / 2.79J / 3.96J / HST.522J Biomaterials-Tissue Interactions

Fall 2009

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MIT20_441JF09_lec02b_ms